PrimPol is required for replication reinitiation after mtDNA damage
Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved September 1, 2017 (received for review April 2, 2017)
Significance
Failure to maintain mtDNA integrity can lead to a wide variety of neuromuscular disorders. Despite its central role in the development of these disorders, many mechanistic details of mtDNA maintenance are still unclear. In the present work, we have studied the role of PrimPol, an unusual primase-polymerase, in mammalian mtDNA maintenance. We report here that PrimPol is specifically required for replication reinitiation after DNA damage. PrimPol synthesizes DNA primers on an ssDNA template, which can be elongated by the mitochondrial replicative polymerase γ, a solution to reprime replication beyond DNA lesions and to facilitate lagging-strand replication. Our findings show that PrimPol has biological relevance for mtDNA maintenance.
Abstract
Eukaryotic PrimPol is a recently discovered DNA-dependent DNA primase and translesion synthesis DNA polymerase found in the nucleus and mitochondria. Although PrimPol has been shown to be required for repriming of stalled replication forks in the nucleus, its role in mitochondria has remained unresolved. Here we demonstrate in vivo and in vitro that PrimPol can reinitiate stalled mtDNA replication and can prime mtDNA replication from nonconventional origins. Our results not only help in the understanding of how mitochondria cope with replicative stress but can also explain some controversial features of the lagging-strand replication.
Acknowledgments
We thank Sandra Chocrón and Maria Martínez-Jiménez for valuable PrimPol-related discussions and work and Mr. Craig Michell (University of Eastern Finland) for language editing. This work was supported by the Jane & Aatos Erkko (JAE) Foundation (R.T.-M. and J.L.O.P.), the Finnish Academy (S.G.), the Wallenberg Foundation (S.W., J.M.E.F., and A.P.), Olle Engkvist Byggmästare Foundation (G.S.), Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (G.C.), and Spanish Ministry of Economy and Competitiveness Grant BFU2015-65880-P (to L.B.).
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© 2017. Published under the PNAS license.
Submission history
Published online: October 9, 2017
Published in issue: October 24, 2017
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Acknowledgments
We thank Sandra Chocrón and Maria Martínez-Jiménez for valuable PrimPol-related discussions and work and Mr. Craig Michell (University of Eastern Finland) for language editing. This work was supported by the Jane & Aatos Erkko (JAE) Foundation (R.T.-M. and J.L.O.P.), the Finnish Academy (S.G.), the Wallenberg Foundation (S.W., J.M.E.F., and A.P.), Olle Engkvist Byggmästare Foundation (G.S.), Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (G.C.), and Spanish Ministry of Economy and Competitiveness Grant BFU2015-65880-P (to L.B.).
Notes
This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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PrimPol is required for replication reinitiation after mtDNA damage, Proc. Natl. Acad. Sci. U.S.A.
114 (43) 11398-11403,
https://doi.org/10.1073/pnas.1705367114
(2017).
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